Regional differences in effects of E-4031  within the sinoatrial node

Kodama, Itsuo; Boyett, Mark R.; Nikmaram, M. R.; Yamamoto, Masahito; Honjo, Haruo; Niwa, Ryoko

doi:10.1152/ajpheart.1999.276.3.h793

Cited by 41 publications

(47 citation statements)

References 15 publications

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“…9 Figure 4, A and B, shows control action potentials for the 2 models when uncoupled. Spontaneous activity of the nodal cell model ceases on I K,r blockade, and the model cell depolarizes to Ϫ38 mV, in accordance with the experimental data 9,20 (Figure 4A), whereas the atrial cell only shows a slight increase in APD ( Figure 4B). When coupled at g j ϭ50 nS ( Figure 4C), the SA nodal cell drives its neighbor atrial cells at 2.1 Hz ( Figure 4D).…”

Section: Computer Simulationssupporting

confidence: 85%

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Atrio-Sinus Interaction Demonstrated by Blockade of the Rapid Delayed Rectifier Current

2002

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Background-Proper pacemaking of the heart requires a specific organization of the sinoatrial (SA) node. The SA node drives the surrounding atrium but needs to be protected from its hyperpolarizing influence, which tends to suppress pacemaker activity. It has been suggested that the hyperpolarizing atrial influence is minimal at the site of the central nodal area. Methods and Results-Atrio-sinus interaction was assessed by specific depolarization of the SA node by blocking the HERG-encoded rapid delayed rectifier current (I K,r ) with the drug E-4031. In the SA node, E-4031 (1 mol/L) changed action potential configuration drastically but never resulted in pacemaker arrest. In the atrium, E-4031 did not affect the membrane resting potential, thereby leaving the normal hyperpolarizing load on the SA node intact. When the SA node was sectioned into strips and subsequently separated from the atrium, spontaneous electrical activity of the strip containing the primary pacemaker ceased on I K,r blockade. When not separated from the atrium, I K,r blockade never resulted in pacemaker arrest. A similar effective atrio-sinus interaction was demonstrated in computer simulations. Conclusions-Our results demonstrate that the atrium provides an effective hyperpolarizing load on the central SA nodal area and is at least one of the controlling mechanisms for normal pacemaking function. The present study can be of help in understanding why patients with long-QT2 syndrome secondary to a mutation in HERG do not show sinus arrest.

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Section: Computer Simulationssupporting

confidence: 85%

“…The resulting membrane resting potential (V rest ) of Ϫ28Ϯ3 mV was comparable to Ϫ33Ϯ6 (nϭ5), found in isolated nodal cells, 9 and Ϫ34 mV, found in central small SA node balls. 20 Cessation of spontaneous activity was never observed in any of the other strips attached to or isolated from the CT.…”

Section: Spatial Distribution Of Effects Of I Kr Blockadementioning

confidence: 94%

Atrio-Sinus Interaction Demonstrated by Blockade of the Rapid Delayed Rectifier Current

2002

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“…When the concentration was raised to 1.0 M, at which there are still negligible effects on other currents, all cells ceased spontaneous activity in both studies. A similar response was found in small balls of tissue isolated from the SA node: with 1.0 M E-4031, activity was abolished in all balls; with 0.1 M E-4031, activity was sometimes extinguished in balls from the central area, but not in those from more peripheral areas (46). The fact that 0.1 M E-4031 abolishes spontaneous activity in smaller, but not in larger, single SA node cells agrees with this observation (59), provided that small cells do indeed stem from the central area of the node and larger cells stem from the periphery.…”

Section: Effect Of Almokalant On Spontaneous Activitysupporting

confidence: 68%

An ionic model for rhythmic activity in small clusters of embryonic chick ventricular cells

Krogh‐Madsen

Schäffer²,

Skriver³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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We recorded transmembrane potential in whole cell recording mode from small clusters (2-4 cells) of spontaneously beating 7-day embryonic chick ventricular cells after 1-3 days in culture and investigated effects of the blockers D-600, diltiazem, almokalant, and Ba 2ϩ . Electrical activity in small clusters is very different from that in reaggregates of several hundred embryonic chick ventricular cells, e.g., TTX-sensitive fast upstrokes in reaggregates vs. TTX-insensitive slow upstrokes in small clusters (maximum upstroke velocity ϳ100 V/s vs. ϳ10 V/s). On the basis of our voltageand current-clamp results and data from the literature, we formulated a Hodgkin-Huxley-type ionic model for the electrical activity in these small clusters. The model contains a Ca 2ϩ current (ICa), three K ϩ currents (IKs, IKr, and IK1), a background current, and a seal-leak current. ICa generates the slow upstroke, whereas IKs, IKr, and IK1 contribute to repolarization. All the currents contribute to spontaneous diastolic depolarization, e.g., removal of the seal-leak current increases the interbeat interval from 392 to 535 ms. The model replicates the spontaneous activity in the clusters as well as the experimental results of application of blockers. Bifurcation analysis and simulations with the model predict that annihilation and single-pulse triggering should occur with partial block of I Ca. Embryonic chick ventricular cells have been used as an experimental model to investigate various aspects of spontaneous beating of cardiac cells, e.g., mutual synchronization, regularity of beating, and spontaneous initiation and termination of reentrant rhythms; our model allows investigation of these topics through numerical simulation.pacemaker; seal-leak current; rapid delayed rectifier potassium current block; slow inward calcium current block; bifurcation analysis SPONTANEOUS ACTIVITY based on generation of the pacemaker potential (spontaneous phase 4, or diastolic, depolarization) is not normally found in adult ventricular muscle in situ, nor is it normally found in single cells freshly isolated from adult ventricular muscle. In contrast, early enough during development, ventricular muscle (or areas of the heart destined to eventually become ventricular muscle) can beat spontaneously (1, 97). Spontaneous electrical activity can also be seen in single cells and in small clusters of cells isolated from the embryonic chick ventricle (10,17,26,49,51,78,95), in the embryonic mouse ventricle (117), and in the neonatal rat ventricle (86).After a couple of days in culture, the electrical activity in an isolated embryonic chick ventricular cell, in a small cluster of a few such cells, or in a sparse monolayer is very different from that in situ or in a reaggregate of hundreds or thousands of cells isolated from the ventricle. For example, when trypsin-dispersed ventricular cells from 7-day embryonic chick hearts are used, the upstroke velocity is much lower in single cells, in small clusters of cells, and in sparse monolayers (17,49,51,95) than...

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“…28,29 If the sinus node is severely affected (eg, ischemia, drug, ageing, etc), the pacemaker reserve function is activated to compensate for the lost ion current. 30 For these reasons, the combined use of LID and NIF may not be suitable, and it is necessary to use a minimal dose of epinephrine to trigger and maintain the reserve potential of the sinus node. In addition, the first dose of NIF should be administered at 50% (0.15 mg·kg -1 ·5 min -1 ) of the normal dose (0.3 mg·kg -1 ·5 min -1 ).…”

Section: Adverse Reactions Of Nif On the Sinus Node With Concomitant mentioning

confidence: 99%

Can Nifekalant Hydrochloride be Used as a First-Line Drug for Cardiopulmonary Arrest (CPA)?

Yoshioka¹,

Amino²,

Morita

et al. 2006

Circ J

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Regional differences in effects of E-4031 within the sinoatrial node

Cited by 41 publications

References 15 publications

Atrio-Sinus Interaction Demonstrated by Blockade of the Rapid Delayed Rectifier Current

Atrio-Sinus Interaction Demonstrated by Blockade of the Rapid Delayed Rectifier Current

An ionic model for rhythmic activity in small clusters of embryonic chick ventricular cells

Can Nifekalant Hydrochloride be Used as a First-Line Drug for Cardiopulmonary Arrest (CPA)?

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